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Renal Physiology

Regulation of Potassium Homeostasis

Biff F. Palmer

AbstractPotassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution ofpotassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassiumhomeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake.Understanding the mechanism and regulatory influences governing the internal distribution and renal clearanceof potassium under normal circumstances can provide a framework for approaching disorders of potassiumcommonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassiummetabolism and is designed to serve as a readily accessible review for the well informed clinician as well as aresource for teaching trainees and medical students.

Clin J Am Soc Nephrol 10: 1050–1060, 2015. doi: 10.2215/CJN.08580813

IntroductionPotassium plays a key role in maintaining cell function.Almost all cells possess an Na1-K1-ATPase, whichpumps Na1 out of the cell and K1 into the cell andleads to a K1 gradient across the cell membrane (K1in.K1out) that is partially responsible for maintaining thepotential difference across the membrane. This poten-tial difference is critical to the function of cells, partic-ularly in excitable tissues, such as nerve and muscle.The body has developed numerous mechanisms for de-fense of serum K1 . These mechanisms serve tomaintain a proper distribution of K1 within the bodyas well as regulate the total body K1 content.

Internal Balance of K1

The kidney is primarily responsible for maintainingtotal body K1 content by matching K1 intake with K1

excretion. Adjustments in renal K1 excretion occurover several hours; therefore, changes in extracellularK1 concentration are initially buffered by movementof K1 into or out of skeletal muscle. The regulation ofK1 distribution between the intracellular and extracel-lular space is referred to as internal K1 balance. Themost important factors regulating this movement undernormal conditions are insulin and catecholamines (1).

After a meal, the postprandial release of insulinfunctions to not only regulate the serum glucoseconcentration but also shift dietary K1 into cells untilthe kidney excretes the K1 load re-establishing K1 ho-meostasis. These effects are mediated through insulinbinding to cell surface receptors, which stimulates glu-cose uptake in insulin-responsive tissues through theinsertion of the glucose transporter protein GLUT4(2,3). An increase in the activity of the Na1-K1-AT-Pase mediates K

1

uptake (Figure 1). In patients withthe metabolic syndrome or CKD, insulin-mediated glu-cose uptake is impaired, but cellular K1 uptake re-mains normal (4,5), demonstrating differentialregulation of insulin-mediated glucose and K1 uptake.

Catecholamines regulate internal K1 distribution, witha-adrenergic receptors impairing and b-adrenergic recep-tors promoting cellular entry of K1. b2-Receptor–inducedstimulation of K1 uptake is mediated by activation of theNa1-K1-ATPase pump. These effects play a role in reg-ulating the cellular release of K1 during exercise (6).Under normal circumstances, exercise is associated

with movement of intracellular K1 into the interstitialspace in skeletal muscle. Increases in interstitial K1

can be as high as 10–12 mM with severe exercise.Accumulation of K1 is a factor limiting the excitabil-ity and contractile force of muscle accounting for thedevelopment of fatigue (7,8). Additionally, increasesin interstitial K1 play a role in eliciting rapid vaso-dilation, allowing for blood flow to increase in exer-cising muscle (9). During exercise, release ofcatecholamines through b2 stimulation limits therise in extracellular K1 concentration that otherwiseoccurs as a result of normal K1 release by contractingmuscle. Although the mechanism is likely to be mul-tifactorial, total body K1 depletion may blunt the ac-cumulation of K1 into the interstitial space, limitingblood flow to skeletal muscle and accounting for theassociation of hypokalemia with rhabdomyolysis.Changes in plasma tonicity and acid–base disorders

also influence internal K1 balance. Hyperglycemialeads to water movement from the intracellular toextracellular compartment. This water movement fa-vors K1 efflux from the cell through the process ofsolvent drag. In addition, cell shrinkage causes intra-cellular K1 concentration to increase, creating a morefavorable concentration gradient for K1 efflux. Min-eral acidosis, but not organic acidosis, can be a causeof cell shift in K1. As recently reviewed, the generaleffect of acidemia to cause K1 loss from cells is notbecause of a direct K1-H1 exchange, but, rather, isbecause of an apparent coupling resulting from ef-fects of acidosis on transporters that normally regu-late cell pH in skeletal muscle (10) (Figure 2).

Department ofInternal Medicine,University of TexasSouthwestern MedicalCenter, Dallas, Texas

Correspondence:Dr. Biff F. Palmer,Department ofInternal Medicine,University of TexasSouthwestern MedicalCenter, 5323 HarryHines Boulevard,Dallas, TX 75390.Email: [email protected]

www.cjasn.org Vol 10 June, 20151050 Copyright © 2015 by the American Society of Nephrology

mailto:[email protected]:[email protected]

Intracellular K1 serves as a reservoir to limit the fall inextracellular K1 concentrations occurring under patho-logic conditions where there is loss of K1 from the body.The efficiency of this effect was shown by military recruitsundergoing training in the summer (11). These subjectswere able to maintain a near-normal serum K1 concentra-tion despite daily sweat K1 loses of .40 mmol and an 11-day cumulative total body K1 deficit of approximately 400mmol.Studies in rats using a K1 clamp technique afforded in-

sight into the role of skeletal muscle in regulating extracel-lular K1 concentration (12). With this technique, insulin isadministered at a constant rate, and K1 is simultaneouslyinfused at a rate designed to prevent any drop in plasmaK1 concentration. The amount of K1 administered is pre-sumed to be equal to the amount of K1 entering the in-tracellular space of skeletal muscle.In rats deprived of K1 for 10 days, the plasma K1 con-

centration decreased from 4.2 to 2.9 mmol/L. Insulin-mediated K1 disappearance declined by more than 90%compared with control values. This decrease in K1 uptakewas accompanied by a .50% reduction in both the activityand expression of muscle Na1-K1-ATPase, suggesting thatdecreased pump activity might account for the decrease ininsulin effect. This decrease in muscle K1 uptake, underconditions of K1 depletion, may limit excessive falls in ex-tracellular K1 concentration that occur under conditions ofinsulin stimulation. Concurrently, reductions in pump

expression and activity facilitate the ability of skeletal muscleto buffer declines in extracellular K1 concentrations by do-nating some component of its intracellular stores.There are differences between skeletal and cardiac

muscle in the response to chronic K1 depletion. Althoughskeletal muscle readily relinquishes K1 to minimize thedrop in plasma K1 concentration, cardiac tissue K1 con-tent remains relatively well preserved. In contrast tothe decline in activity and expression of skeletal muscleNa1 -K1 -ATPase, cardiac Na1 -K1 -ATPase pool size

Figure 1. | The cell model illustrates b2-adrenergic and insulin-mediated regulatory pathways for K1 uptake. b2-Adrenergic andinsulin both lead to K1 uptake by stimulating the activity of theNa1-K1-ATPase pump primarily in skeletal muscle, but they do sothrough different signaling pathways. b2-Adrenergic stimulationleads to increased pump activity through a cAMP- and proteinkinase A (PKA)–dependent pathway. Insulin binding to its receptorleads to phosphorylation of the insulin receptor substrate pro-tein (IRS-1), which, in turn, binds to phosphatidylinositide3-kinase (PI3-K). The IRS-1–PI3-K interaction leads to activation of3-phosphoinositide–dependent protein kinase-1 (PDK1). The stimulatoryeffect of insulin on glucose uptake and K1 uptake diverge at this point.An Akt-dependent pathway is responsible for membrane insertion ofthe glucose transporterGLUT4,whereas activation of atypical proteinkinase C (aPKC) leads to membrane insertion of the Na1-K1-ATPasepump (reviewed in ref. 3).

Figure 2. | The effect of metabolic acidosis on internal K1 balance inskeletal muscle. (A) In metabolic acidosis caused by inorganic anions(mineral acidosis), the decrease in extracellular pH will decrease therate of Na1-H1 exchange (NHE1) and inhibit the inward rate of Na1

-3HCO3 cotransport (NBCe1 and NBCe2). The resultant fall in in-tracellular Na1 will reduce Na1-K1-ATPase activity, causing a netloss of cellular K1. In addition, the fall in extracellular HCO3 concen-tration will increase inward movement of Cl2 by Cl-HCO2 exchange,further enhancing K1 efflux by K1-Cl2 cotransport. (B) Loss of K1 fromthecell ismuch smaller inmagnitude inmetabolic acidosis causedbyanorganic acidosis. In this setting, there is a strong inward flux of the or-ganic anion and H1 through the monocarboxylate transporter (MCT;MCT1 and MCT4). Accumulation of the acid results in a larger fall inintracellular pH, thereby stimulating inward Na1 movement by way ofNa1-H1 exchange and Na1-3HCO3 cotransport. Accumulation of in-tracellular Na1 maintains Na1-K1-ATPase activity, thereby mini-mizing any change in extracellular K1 concentration.

Clin J Am Soc Nephrol 10: 1050–1060, June, 2015 Normal Potassium Homeostasis, Palmer 1051

increases in K1-deficient animals. This difference explainsthe greater total K1 clearance capacity after the acute ad-ministration of intravenous KCl to rats fed a K1-free dietfor 2 weeks compared with K1-replete controls (13,14).Cardiac muscle accumulates a considerable amount ofK1 in the setting of an acute load. When expressed on aweight basis, the cardiac capacity for K1 uptake is compa-rable with that of skeletal muscle under conditions of K1

depletion and may actually exceed skeletal muscle undercontrol conditions.

Renal Potassium HandlingPotassium is freely filtered by the glomerulus. The bulk

of filtered K1 is reabsorbed in the proximal tubule andloop of Henle, such that less than 10% of the filteredload reaches the distal nephron. In the proximal tubule,K1 absorption is primarily passive and proportional toNa1 and water (Figure 3). K1 reabsorption in the thickascending limb of Henle occurs through both transcellularand paracellular pathways. The transcellular componentis mediated by K1 transport on the apical membraneNa1-K1-2Cl2 cotransporter (Figure 4). K1 secretion beginsin the early distal convoluted tubule and progressivelyincreases along the distal nephron into the cortical collect-ing duct (Figure 5). Most urinary K1 can be accounted forby electrogenic K1 secretion mediated by principal cells inthe initial collecting duct and the cortical collecting duct(Figure 6). An electroneutral K1 and Cl2 cotransportmechanism is also present on the apical surface of the

distal nephron (15). Under conditions of K1 depletion, re-absorption of K1 occurs in the collecting duct. This processis mediated by upregulation in the apically located H1-K1

-ATPase on a-intercalated cells (16) (Figure 7).Under most homeostatic conditions, K1 delivery to the

distal nephron remains small and is fairly constant. By con-trast, the rate of K1 secretion by the distal nephron variesand is regulated according to physiologic needs. The cellulardeterminants of K1 secretion in the principal cell include theintracellular K1 concentration, the luminal K1 concentration,the potential (voltage) difference across the luminal mem-brane, and the permeability of the luminal membrane forK1. Conditions that increase cellular K1 concentration, de-crease luminal K1 concentration, or render the lumen moreelectronegative will increase the rate of K1 secretion. Con-ditions that increase the permeability of the luminal mem-brane for K1 will increase the rate of K1 secretion. Twoprincipal determinants of K1 secretion are mineralocorticoidactivity and distal delivery of Na1 and water.Aldosterone is the major mineralocorticoid in humans

and affects several of the cellular determinants discussedabove, leading to stimulation of K1 secretion. First, aldo-sterone increases intracellular K1 concentration by stimu-lating the activity of the Na1-K1-ATPase in the basolateralmembrane. Second, aldosterone stimulates Na1 reabsorp-tion across the luminal membrane, which increases theelectronegativity of the lumen, thereby increasing the elec-trical gradient favoring K1 secretion. Lastly, aldosteronehas a direct effect on the luminal membrane to increase K1

permeability (17).

Figure 3. | A cell model for K1 transport in the proximal tubule. K1

reabsorption in the proximal tubule primarily occurs through theparacellular pathway. Active Na1 reabsorption drives net fluid re-absorption across the proximal tubule, which in turn, drives K1 re-absorption through a solvent drag mechanism. As fluid flows downthe proximal tubule, the luminal voltage shifts from slightly negativeto slightly positive. The shift in transepithelial voltage provides anadditional driving force favoring K1 diffusion through the low-resistance paracellular pathway. Experimental studies suggest thatthere may be a small component of transcellular K1 transport; how-ever, the significance of this pathway is not known. K1 uptake throughtheNa1-K1-ATPase pump can exit the basolateralmembrane througha conductive pathway or coupled to Cl2. An apically located K1

channel functions to stabilize the cell negative potential, particularlyin the setting of Na1-coupled cotransport of glucose and amino acids,which has a depolarizing effect on cell voltage.

Figure 4. | A cell model for K1 transport in the thick ascending limbof Henle. K1 reabsorption occurs by both paracellular and trans-cellular mechanisms. The basolateral Na1-K1-ATPase pump main-tains intracellular Na1 low, thus providing a favorable gradient todrive the apically located Na1-K1-2Cl2 cotransporter (an example ofsecondary active transport). The apically located renal outer medul-lary K1 (ROMK) channel provides a pathway for K1 to recyclefrom cell to lumen, and ensures an adequate supply of K1 to sustainNa1-K1-2Cl2 cotransport. This movement through ROMK createsa lumen-positive voltage, providing a driving force for passive K1

reabsorption through the paracellular pathway. Some of the K1 enteringthe cell through the cotransporter exits the cell across the basolateralmembrane, accounting for transcellular K1 reabsorption. K1 can exitthe cell through a conductive pathway or in cotransport with Cl2.ClC-Kb is the primary pathway for Cl2 efflux across the basolateralmembrane.

1052 Clinical Journal of the American Society of Nephrology

A second principal determinant affecting K1 secretion isthe rate of distal delivery of Na1 and water. Increaseddistal delivery of Na1 stimulates distal Na1 absorption,which will make the luminal potential more negativeand, thus, increase K1 secretion. Increased flow ratesalso increase K1 secretion. When K1 is secreted in thecollecting duct, the luminal K1 concentration rises, whichdecreases the diffusion gradient and slows additional K1

secretion. At higher luminal flow rates, the same amountof K1 secretion will be diluted by the larger volume suchthat the rise in luminal K1 concentration will be less. Thus,increases in the distal delivery of Na1 and water stimulateK1 secretion by lowering luminal K1 concentration andmaking the luminal potential more negative.

Two populations of K1 channels have been identified in thecells of the cortical collecting duct. The renal outer medullaryK1 (ROMK) channel is considered to be the major K1-secretorypathway. This channel is characterized by having low con-ductance and a high probability of being open under phys-iologic conditions. The maxi-K1 channel (also known as thelarge-conductance K1 [BK] channel) is characterized by alarge single channel conductance and quiescence in the basalstate and activation under conditions of increased flow (18).In addition to increased delivery of Na1 and dilution ofluminal K1 concentration, recruitment of maxi-K1 channelscontributes to flow-dependent increased K1 secretion. RenalK1 channels are subjects of extensive reviews (19–21).

Figure 5. | A cell model for K1 transport in the distal convolutedtubule (DCT). In the early DCT, luminal Na1 uptake is mediated bythe apically located thiazide-sensitive Na1-Cl2 cotransporter. Thetransporter is energized by the basolateral Na1-K1-ATPase, whichmaintains intracellular Na1 concentration low, thus providing a fa-vorable gradient for Na1 entry into the cell through secondary activetransport. The cotransporter is abundantly expressed in the DCT1but progressively declines along the DCT2. ROMK is expressedthroughout the DCTand into the cortical collecting duct. Expressionof the epithelial Na1 channel (ENaC), which mediates amiloride-sensitive Na1 absorption, begins in the DCT2 and is robustly ex-pressed throughout the downstream connecting tubule and corticalcollecting duct. The DCT2 is the beginning of the aldosterone-sensitive distal nephron (ASDN) as identified by the presence of boththe mineralocorticoid receptor and the enzyme 11b-hydroxysteroiddehydrogenase II. This enzyme maintains the mineralocorticoidreceptor free to only bind aldosterone by metabolizing cortisol to cor-tisone, the latter of which has no affinity for the receptor. Electrogenic-mediated K1 transport begins in the DCT2with the combined presenceof ROMK, ENaC, and aldosterone sensitivity. Electroneutral K1-Cl2

cotransport is present in the DCT and collecting duct. Conditionsthat cause a low luminal Cl2 concentration increase K1 secretionthrough this mechanism, which occurs with delivery of poorly re-absorbable anions, such as sulfate, phosphate, or bicarbonate.

Figure 6. | The cell that is responsible for K1 secretion in the initialcollecting duct and the cortical collecting duct is the principal cell.This cell possesses a basolateral Na1-K1-ATPase that is responsiblefor the active transport of K1 from the blood into the cell. The resultanthigh cell K1 concentration provides a favorable diffusion gradient formovement of K1 from the cell into the lumen. In addition to estab-lishing a high intracellular K1 concentration, activity of this pumplowers intracellular Na1 concentration, thus maintaining a favorablediffusion gradient for movement of Na1 from the lumen into the cell.Both the movements of Na1 and K1 across the apical membraneoccur through well defined Na1 and K1 channels.

Figure 7. | Reabsorption of HCO3 in the distal nephron is mediatedby apical H1 secretion by the a-intercalated cell. Two transporterssecrete H1, a vacuolar H1-ATPase and an H1-K1-ATPase. The H1-K1

-ATPase uses the energy derived from ATP hydrolysis to secrete H1

into the lumen and reabsorb K1 in an electroneutral fashion. Theactivity of the H1-K1-ATPase increases in K1 depletion and, thus,provides a mechanism by which K1 depletion enhances both col-lecting duct H1 secretion and K1 absorption.


The effect of increased tubular flow to activate maxi-K1

channels may be mediated by changes in intracellularCa21 concentration (22). The channel is Ca21-activated,and an acute increase in flow increases intracellular Ca21

concentrations in the principal cell. It has been suggestedthat the central cilium (a structure present in principalcells) may facilitate transduction of signals of increasedflow to increased intracellular Ca21 concentration. In cul-tured cells, bending of primary cilia results in a transientincrease in intracellular Ca21, an effect blocked by anti-bodies to polycystin 2 (23). Although present in nearlyall segments of the nephron, the maxi-K channel hasbeen identified as the mediator of flow-induced K1 secre-tion in the distal nephron and cortical collecting duct (24).Development of hypokalemia in type II Bartter syn-

drome illustrates the importance of maxi-K1 channels inrenal K1 excretion (25). Patients with type II Bartter syn-drome have a loss-of-function mutation in ROMK mani-festing with clinical features of the disease in the perinatalperiod. ROMK provides the pathway for recycling of K1

across the apical membrane in the thick ascending limbof Henle. This recycling generates a lumen-positive poten-tial that drives the paracellular reabsorption of Ca21 andMg21 and provides luminal K1 to the Na1-K1-2Cl2 co-transporter (Figure 4).Mutations in ROMK decrease NaCl and fluid reabsorption

in the thick limb, mimicking a loop diuretic effect, whichcauses volume depletion. Despite the increase in distal Na1

delivery, K1 wasting is not consistently observed, becauseROMK is also the major K1-secretory pathway for regulatedK1 excretion in the collecting duct. In fact, in the perinatalperiod, infants with this form of Bartter syndrome oftenexhibit a transient hyperkalemia consistent with loss of func-tion of ROMK in the collecting duct. However, over time,these patients develop hypokalemia as a result of increasedflow-mediated K1 secretion through maxi-K1 channels.Studies in an ROMK-deficient mouse model of type II Barttersyndrome are consistent with this mechanism (26). Thetransient hyperkalemia observed in the perinatal period islikely related to the fact that ROMK channels are function-ally expressed earlier than maxi-K1 channels during thecourse of development.In this regard, growing infants and children are in a state

of positive K1 balance, which correlates with growth andincreasing cell number. Early in development, there is alimited capacity of the distal nephron to secrete K1 becauseof a paucity of both apically located ROMK and maxi-K1

channels. The increase in K1-secretory capacity with matu-ration is initially a result of increased expression of ROMK.Several weeks later, maxi-K1 channel expression develops,allowing for flow-mediated K1 secretion to occur (reviewedin ref. 27). The limitation in distal K1 secretion is channel-specific, because the electrochemical gradient favoring K1

secretion, as determined by activity of the Na1-K1-ATPaseand Na1 reabsorption, is not limiting. Additionally, in-creased flow rates are accompanied by appropriate increasesin Na1 reabsorption and intracellular Ca21 concentrations inthe distal nephron, despite the absence of stimulatory effecton K1 secretion (28). Activity of the H1- K1-ATPase, whichcouples K1 reabsorption to H1 secretion in intercalatedcells, is similar in newborns and adults. K1 reabsorptionthrough this pump, combined with decreased expression

of K1-secretory channels, helps maintain a state of positiveK1 balance during somatic growth after birth. These featuresof distal K1 handling by the developing kidney are a likelyexplanation for the high incidence of nonoliguric hyperkale-mia in preterm infants (29).Another physiologic state characterized by a period of

positive K1 balance is pregnancy, where approximately300 mEq K1 is retained (30). High circulating levels ofprogesterone may play a role in this adaptation throughstimulatory effects on K1 and H1 transport by the H1-K1

a2-ATPase isoform in the distal nephron (31).In addition to stimulating maxi-K1 channels, increased

tubular flow has been shown to stimulate Na1 absorptionthrough the epithelial Na1 channel (ENaC) in the collect-ing duct. This increase in absorption not only is because ofincreased delivery of Na1, but also seems to be the resultof mechanosensitive properties intrinsic to the channel. In-creased flow creates a shear stress that activates ENaCs byincreasing channel open probability (32,33).It has been hypothesized that biomechanical regulation of

renal tubular Na1 and K1 transport in the distal nephronmay have evolved as a response to defend against suddenincreases in extracellular K1 concentration that occur in re-sponse to ingestion of K1-rich diets typical of early verte-brates (22). According to this hypothesis, an increase in GFRafter a protein-rich meal would lead to an increase in distalflow activating the ENaC, increasing intracellular Ca21 con-centration, and activating maxi-K1 channels. These eventswould enhance K1 secretion, thus providing a buffer toguard against development of hyperkalemia.In patients with CKD, loss of nephron mass is counter-

balanced by an adaptive increase in the secretory rate of K1

in remaining nephrons such that K1 homeostasis is gener-ally well maintained until the GFR falls below 15–20 ml/min (34). The nature of the adaptive process is thought tobe similar to the adaptive process that occurs in responseto high dietary K1 intake in normal subjects (35). ChronicK1 loading in animals augments the secretory capacity ofthe distal nephron, and, therefore, renal K1 excretion issignificantly increased for any given plasma K1 level. In-creased K1 secretion under these conditions occurs in as-sociation with structural changes characterized by cellularhypertrophy, increased mitochondrial density, and prolif-eration of the basolateral membrane in cells in the distalnephron and principal cells of the collecting duct. In-creased serum K1 and mineralocorticoids independentlyinitiate the amplification process, which is accompanied byan increase in Na1-K1-ATPase activity.

Aldosterone ParadoxUnder conditions of volume depletion, activation of the

renin-angiotensin system leads to increased aldosteronerelease. The increase in circulating aldosterone stimulatesrenal Na1 retention, contributing to the restoration of ex-tracellular fluid volume, but occurs without a demonstra-ble effect on renal K1 secretion. Under condition ofhyperkalemia, aldosterone release is mediated by a directeffect of K1 on cells in the zona glomerulosa. The subse-quent increase in circulating aldosterone stimulates renalK1 secretion, restoring the serum K1 concentration to nor-mal, but does so without concomitant renal Na1 retention.


The ability of aldosterone to signal the kidney to stim-ulate salt retention without K1 secretion in volume de-pletion and stimulate K1 secretion without salt retentionin hyperkalemia has been referred to as the aldosteroneparadox (36). In part, this ability can be explained by thereciprocal relationship between urinary flow rates and dis-tal Na1 delivery with circulating aldosterone levels. Underconditions of volume depletion, proximal salt and waterabsorption increase, resulting in decreased distal deliveryof Na1 and water. Although aldosterone levels are in-creased, renal K1 excretion remains fairly constant, be-cause the stimulatory effect of increased aldosterone iscounterbalanced by the decreased delivery of filtrate tothe distal nephron. Under condition of an expanded extra-cellular fluid volume, distal delivery of filtrate is increasedas a result of decreased proximal tubular fluid reabsorp-tion. Once again, renal K1 excretion remains relativelyconstant in this setting, because circulating aldosteronelevels are suppressed. It is only under pathophysiologicconditions that increased distal Na1 and water deliveryare coupled to increased aldosterone levels. Renal K1

wasting will occur in this setting (37) (Figure 8).Renal K1 secretion also remains stable during changes

in flow rate resulting from variations in circulating vaso-pressin. In this regard, vasopressin has a stimulatory effecton renal K1 secretion (38,39). This kaliuretic property mayserve to oppose a tendency to K1 retention under condi-tions of antidiuresis when a low-flow rate-dependent fallin distal tubular K1 secretion might otherwise occur. Incontrast, suppressed endogenous vasopressin leads to de-creased activity of the distal K1-secretory mechanism, thuslimiting excessive K losses under conditions of full hydra-tion and water diuresis.Although the inverse relationship between aldosterone

levels and distal delivery of salt and water serves to keeprenal K1 excretion independent of volume status, recentreviews have suggested a more complex mechanism cen-tered on the with no lysine [K] 4 (WNK4) protein kinase in

the distal nephron (40,41). WNK4 is one of four membersof a family of serine-threonine kinases each encoded by adifferent gene and characterized by the atypical place-ment of the catalytic lysine residue that is present inmost other protein kinases. Inactivating mutations inWNK4 lead to development of pseudohypoaldosteronismtype II (PHAII; Gordon syndrome). This disorder is in-herited in an autosomal dominant fashion and is charac-terized by hypertension and hyperkalemia (42).Circulating aldosterone levels are low, despite the pres-ence of hyperkalemia. Thiazide diuretics are particularlyeffective in treating both the hypertension and hyperkale-mia (43).Wild-type WNK4 acts to reduce surface expression of the

thiazide-sensitive Na1-Cl2 cotransporter and also stimu-lates clathrin-dependent endocytosis of ROMK in the col-lecting duct (44,45). The inactivating mutation of WNK4responsible for PHAII leads to increased cotransporter ac-tivity and further stimulates endocytosis of ROMK. Thenet effect is increased NaCl reabsorption combined withdecreased K1 secretion. Mutated WNK4 also enhancesparacellular Cl2 permeability caused by increased phos-phorylation of claudins, which are tight junction proteinsinvolved in regulating paracellular ion transport (46). Inaddition to increasing Na1 retention, this change in per-meability further impairs K1 secretion, because the lumen-negative voltage, which normally serves as a driving forcefor K1 secretion, is dissipated.Because development of hypertension and hyperkalemia

resulting from the PHAII-mutated WNK4 protein can beviewed as an exaggerated response to a reduction in extra-cellular fluid volume (salt retention without increased K1

secretion), it has been proposed that wild-type WNK4 mayact as a molecular switch determining balance between renalNaCl reabsorption and K1 secretion (45,47). Under condi-tions of volume depletion, the switch would be altered in amanner reminiscent of the PHAII mutant such that NaClreabsorption is increased, but K1 secretion is further

Figure 8. | Under normal circumstances, delivery of Na1 to the distal nephron is inversely associated with serum aldosterone levels. For thisreason, renal K1 excretion is kept independent of changes in extracellular fluid volume. Hypokalemia caused by renal K1 wasting can beexplained by pathophysiologic changes that lead to coupling of increased distal Na1 delivery and aldosterone or aldosterone-like effects.When approaching the hypokalemia caused by renal K1 wasting, one must determine whether the primary disorder is an increase in min-eralocorticoid activity or an increase in distal Na1 delivery. EABV, effective arterial blood volume.


inhibited. However, when increased serum K1 concentrationoccurs in the absence of volume depletion, WNK4 alterationsresult in maximal renal K1 secretion without Na1 retention.Angiotensin II (AII) has emerged as an important

modulator of this switch. Under conditions of volumedepletion, AII and aldosterone levels are increased (Figure9). In addition to effects leading to enhanced NaCl reab-sorption in the proximal tubule, AII activates the Na1-Cl2

cotransporter in a WNK4-dependent manner, and it is pri-marily located in the initial part of the distal convolutedtubule (DCT; DCT1) (48,49). AII also activates ENaC,which is found in the aldosterone-sensitive distal nephron(ASDN) comprised of the second segment of the DCT(DCT2), the connecting tubule, and the collecting duct(50). The activation of ENaC by AII is additive to that ofaldosterone (51). In this manner, AII and aldosterone act inconcert to stimulate Na1 retention. At the same time, AII in-hibits ROMK by both WNK4-dependent and -independentmechanisms (52,53). This inhibitory effect on ROMK alongwith decreased Na1 delivery to the collecting duct broughtabout by AII stimulation of Na1 reabsorption in the prox-imal nephron, and DCT1 allows for simultaneous Na1 con-servation without K1 wasting.Hyperkalemia, or an increase in dietary K1 intake, can

increase renal K1 secretion independent of change in min-eralocorticoid activity and without causing volume reten-tion. This effect was shown in Wistar rats fed a diet verylow in NaCl and K1 for several days and given a pharma-cologic dose of deoxycorticosterone to ensure a constantand nonvariable effect of mineralocorticoids (54,55).After a KCl load administered into the peritoneal cavity,two distinct phases were noted. In the first 2 hours, therewas a large increase in the rate of renal K1 excretion that

was largely caused by an increase in the K1 concentrationin the cortical collecting duct. During this early phase, flowthrough the collecting duct increased only slightly, sug-gesting that changes in K1 concentration were largelycaused by an increase in K1-secretory capacity of the col-lecting duct. This effect would be consistent with knowneffects of dietary supplementation of K1 to increase chan-nel density of both ROMK and maxi-K1 channels (56).In the subsequent 4 hours, renal K1 excretion continued

to be high, but during this second phase, the kaliuresis wasmostly accounted for by increased flow through the col-lecting duct. The increased flow was attributed to an in-hibitory effect of increased interstitial K1 concentration onreabsorption of NaCl in the upstream ascending limb ofHenle, an effect supported by microperfusion studies inthe past (57,58). The timing of the two phases is presum-ably important, because higher flows would be most effec-tive in promoting kaliuresis only after establishment ofincreased channel density. Although older studies are con-sistent with decreased Na1 absorption in the thick limband proximal nephron after increased K1 intake, inhibi-tory effects in these high-capacity segments lack the pre-cision and timing necessary to ensure that downstreamdelivery of Na1 is appropriate to maximally stimulateK1 secretion and at the same time, not be excessive, pre-disposing to volume depletion, particularly in the settingof a low Na1 diet (57–59).The low-capacity nature of the DCT and its location im-

mediately upstream from the ASDN make this segment amore likely site for changes in dietary K1 intake to modulateNa1 transport and ensure that downstream delivery of Na1

is precisely the amount needed to ensure maintenance of K1

homeostasis without causing unwanted effects on volume.

Figure 9. | The aldosterone paradox refers to the ability of the kidney to stimulateNaCl retentionwithminimal K1 secretion under conditionsof volume depletion and maximize K1 secretion without Na1 retention in hyperkalemia. With volume depletion (left panel), increasedcirculating angiotensin II (AII) levels stimulate the Na1-Cl2 cotransporter in the early DCT. In the ASDN, AII along with aldosterone stimulatethe ENaC. In this latter segment, AII exerts an inhibitory effect on ROMK, thereby providing a mechanism to maximally conserve salt andminimize renal K1 secretion. When hyperkalemia or increased dietary K1 intake occurs with normovolemia (right panel), low circulatinglevels of AII or direct effects of K1 lead to inhibition of Na1-Cl2 cotransport activity along with increased activity of ROMK. As a result, Na1

delivery to the ENaC is optimized for the coupled electrogenic secretion of K1 through ROMK. As discussed in the text, with no lysine [K] 4(WNK4) proteins are integrally involved in the signals by which the paradox is brought about. It should be emphasized the WNK proteins arepart of a complex signaling network still being fully elucidated. The interested reader is referred to several recent reviews and advancements onthis subject (48,51,91–93).


In this regard, increased dietary K1 intake leads to an in-hibitory effect on Na1 transport in this segment and does sothrough effects on WNK1, another member of the WNKfamily of kinases (60,61). WNK1 is ubiquitously expressedthroughout the body in multiple spliced forms. Bycontrast, a shorter WNK1 transcript lacking the amino ter-minal 1–437 amino acids of the long transcript is highly ex-pressed in the kidney but not other tissues, and it is referredto as kidney-specific WNK1 (KS-WNK1). KS-WNK1 is re-stricted to the DCT and part of the connecting duct andfunctions as a physiologic antagonist to the actions of longWNK1. Changes in the ratio of KS-WNK1 and long WNK1in response to dietary K1 contribute to the physiologic reg-ulation of renal K1 excretion (62–65).Under normal circumstances, long WNK1 prevents the

ability of WNK4 to inhibit activity of the Na1-Cl2 cotrans-porter in the DCT. Thus, increased activity of long WNK1leads to a net increase in NaCl reabsorption. Dietary K1

loading increases the abundance of KS-WNK1. IncreasedKS-WNK1 antagonizes the inhibitory effect of long WNK1on WNK4. The net effect is inhibition of Na1-Cl2 cotrans-port in the DCT and increased Na1 delivery to more distalparts of the tubule. In addition, increased KS-WNK1 an-tagonizes the effect of long WNK1 to stimulate endocyto-sis of ROMK. Furthermore, KS-WNK1 exerts a stimulatoryeffect on the ENaC. Thus, increases in KS-WNK1 in re-sponse to dietary K1 loading facilitate K1 secretionthrough the combined effects of increased Na1 deliverythrough downregulation of Na1-Cl2 cotransport in theDCT, increased electrogenic Na1 reabsorption throughthe ENaC, and greater abundance of ROMK.Increased aldosterone levels in response to a high K1 diet

lead to effects that complement the effects of KS-WNK1(66,67). The serum- and glucocorticoid-dependent proteinkinase (SGK1) is an immediate transcriptional target of al-dosterone binding to the mineralocorticoid receptor. Activa-tion of SGK1 leads to phosphorylation of WNK4, resultingin a loss of the ability of WNK4 to inhibit ROMK and theENaC (66,68). Aldosterone-induced activation of SGK1 alsoleads to increased ENaC expression and activity by causingthe phosphorylation of ubiquitin protein ligase Nedd4–2.Phosphorylated Nedd4–2 results in less retrieval of ENaCfrom the apical membrane (69). It should be emphasizedthat the absence of AII is a critical factor in the ability ofhigh K1 intake to bring about the changes necessary to fa-cilitate K1 secretion without excessive Na1 reabsorption.

Role in HypertensionChanges in KS-WNK1 and long WNK1 that occur in

response to dietary K1 intake affect renal Na1 handlingin a way that may be of importance in the observed re-lationship between dietary K1 intake and hypertension.Epidemiologic studies established that K1 intake is in-versely related to the prevalence of hypertension (70). Inaddition, K1 supplements and avoidance of hypokalemialowers BP in hypertensive subjects. By contrast, BP in-creases in hypertensive subjects placed on a low K1 diet.This increase in BP is associated with increased renal Na1

reabsorption (71).K1 deficiency increases the ratio of long WNK1 to

KS-WNK1. LongWNK1 is associated with increased retrieval

of ROMK, thus providing an appropriate response to limitK1 secretion. However, long WNK1 also leads to a stimu-latory effect on ENaC activity as well as releasing the in-hibitory effect of WNK4 on Na1 reabsorption mediated bythe NaCl cotransporter in the DCT (72,73). These effectssuggest that reductions in K1 secretion under conditionsof K1 deficiency will occur at the expense of increased Na1

retention.Renal conservation of K1 and Na1 under conditions of K1

deficiency may be considered an evolutionary adaptation,because dietary K1 and Na1 deficiency likely occurred to-gether for early humans (74). However, such an effect ispotentially deleterious in our present setting, because evolu-tion has seen a large increase in the ratio of dietary intake ofNa1 versus K1. The effects of an increased ratio of WNK1 toKS-WNK1 in the kidney under conditions of modern dayhigh Na1/low K1 diet could be central to the pathogenesisof salt-sensitive hypertension (75).

Enteric Sensor of K1

There is evidence to support the existence of enteric solutesensors capable of responding to dietary Na1, K1, and phos-phate that signal the kidney to rapidly alter ion excretion orreabsorption (76–78). In experimental animals, and usingprotocols to maintain identical plasma K1 concentration,the kaliuretic response to a K1 load is greater when givenas a meal compared with an intravenous infusion (79). Thesestudies suggest that dietary K1 intake through a splanchnicsensing mechanism can signal increases in renal K1 excre-tion independent of changes in plasma K1 concentration oraldosterone (reviewed in ref. 80).Although the precise signaling mechanism is not known,

recent studies suggest that the renal response may bebecause of rapid and nearly complete dephosphorylation ofthe Na1-Cl2 cotransporter in the DCT, causing decreasedactivity of the transporter and, thus, enhancing delivery ofNa1 to the ASDN (81,82). In these studies, gastric deliveryof K1 led to dephosphorylation of the cotransporter withinminutes independent of aldosterone and based on in vitrostudies, independent of changes in extracellular K1 con-centration. The temporally associated increase in renal K1

excretion results from a more favorable electrochemicaldriving force caused by the downstream shift in Na1 re-absorption from the DCT to the ENaC in the ASDN as wellas increased maxi-K1 channel K1 secretion brought on byincreased flow. This rapid natriuretic response to increasesin dietary K1 intake is consistent with the BP-loweringeffect of K1-rich diets discussed earlier.

Circadian Rhythm of K1 SecretionDuring a 24-hour period, urinary K1 excretion varies in

response to changes in activity and fluctuations in K1 intakecaused by the spacing of meals. However, even when K1

intake and activity are evenly spread over a 24-hour period,there remains a circadian rhythm whereby K1 excretion islower at night and in the early morning hours and then in-creases in the afternoon (83–86). This circadian pattern resultsfrom changes in intratubular K1 concentration in the collect-ing duct as opposed to variations in urine flow rate (87).In the mouse distal nephron, a circadian rhythm exists

for gene transcripts that encode proteins involving K1


secretion (88). Gene expression of ROMK is greater duringperiods of activity, whereas expression of the H1-K1-AT-Pase is higher during rest, which correspond to periodswhen renal K1 excretion is greater and less, respectively(89). Changes in plasma aldosterone levels may play a con-tributory role, because circadian rhythm of glucocorticoidsynthesis and secretion has been described in the adrenalgland. In addition, expression of clock genes within cells ofthe distal nephron suggests that a pacemaker function reg-ulating K1 transport may be an intrinsic component of thekidney that is capable of operating independent of outsideinfluence.The clinical significance of this rhythmicity in K1 and

other electrolyte secretions is not known. Evidence sug-gests that dysregulation of circadian rhythms may contrib-ute to a lack of nocturnal decline in BP, with eventualdevelopment of sustained hypertension as well as acceler-ated CKD and cardiovascular disease (85,90).

DisclosuresNone.

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